Patterns of asymmetry and energy cost generated from predictive simulations of hemiparetic gait.

Hemiparesis, defined as unilateral muscle weakness, often occurs in people post-stroke or people with cerebral palsy, however it is difficult to understand how this hemiparesis affects movement patterns as it often presents alongside a variety of other neuromuscular impairments. Predictive musculoskeletal modeling presents an opportunity to investigate how impairments affect gait performance assuming a particular cost function. Here, we use predictive simulation to quantify the spatiotemporal asymmetries and changes to metabolic cost that emerge when muscle strength is unilaterally reduced and how reducing spatiotemporal symmetry affects metabolic cost. We modified a 2-D musculoskeletal model by uniformly reducing the peak isometric muscle force unilaterally. We then solved optimal control simulations of walking across a range of speeds by minimizing the sum of the cubed muscle excitations. Lastly, we ran additional optimizations to test if reducing spatiotemporal asymmetry would result in an increase in metabolic cost. Our results showed that the magnitude and direction of effort-optimal spatiotemporal asymmetries depends on both the gait speed and level of weakness. Also, the optimal speed was 1.25 m/s for the symmetrical and 20% weakness models but slower (1.00 m/s) for the 40% and 60% weakness models, suggesting that hemiparesis can account for a portion of the slower gait speed seen in people with hemiparesis. Modifying the cost function to minimize spatiotemporal asymmetry resulted in small increases (~4%) in metabolic cost. Overall, our results indicate that spatiotemporal asymmetry may be optimal for people with hemiparesis. Additionally, the effect of speed and the level of weakness on spatiotemporal asymmetry may help explain the well-known heterogenous distribution of spatiotemporal asymmetries observed in the clinic. Future work could extend our results by testing the effects of other neuromuscular impairments on optimal gait strategies, and therefore build a more comprehensive understanding of the gait patterns observed in clinical populations.

A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

Lower Extremity Inverse Kinematics Results Differ Between Inertial Measurement Unit- and Marker-Derived Gait Data.

In-lab, marker-based gait analyses may not represent real-world gait. Real-world gait analyses may be feasible using inertial measurement units (IMUs) in combination with open-source data processing pipelines (OpenSense). Before using OpenSense to study real-world gait, we must determine whether these methods estimate joint kinematics similarly to traditional marker-based motion capture (MoCap) and differentiate groups with clinically different gait mechanics. Healthy young and older adults and older adults with knee osteoarthritis completed this study. We captured MoCap and IMU data during overground walking at 2 speeds. MoCap and IMU kinematics were computed with OpenSim workflows. We tested whether sagittal kinematics differed between MoCap and IMU, whether tools detected between-group differences similarly, and whether kinematics differed between tools by speed. MoCap showed more anterior pelvic tilt (0%-100% stride) and joint flexion than IMU (hip: 0%-38% and 61%-100% stride; knee: 0%-38%, 58%-89%, and 95%-99% stride; and ankle: 6%-99% stride). There were no significant tool-by-group interactions. We found significant tool-by-speed interactions for all angles. While MoCap- and IMU-derived kinematics differed, the lack of tool-by-group interactions suggests consistent tracking across clinical cohorts. Results of the current study suggest that IMU-derived kinematics with OpenSense may enable reliable evaluation of gait in real-world settings.

The effects of posture on the three-dimensional gait mechanics of human walking in comparison with walking in bipedal chimpanzees.

Humans walk with an upright posture on extended limbs during stance and with a double-peaked vertical ground reaction force. Our closest living relatives, chimpanzees, are facultative bipeds that walk with a crouched posture on flexed, abducted hind limbs and with a single-peaked vertical ground reaction force. Differences in human and bipedal chimpanzee three-dimensional (3D) kinematics have been well quantified, yet it is unclear what the independent effects of using a crouched posture are on 3D gait mechanics for humans, and how they compare with chimpanzees. Understanding the relationships between posture and gait mechanics, with known differences in morphology between species, can help researchers better interpret the effects of trait evolution on bipedal walking. We quantified pelvis and lower limb 3D kinematics and ground reaction forces as humans adopted a series of upright and crouched postures and compared them with data from bipedal chimpanzee walking. Human crouched-posture gait mechanics were more similar to that of bipedal chimpanzee gait than to normal human walking, especially in sagittal plane hip and knee angles. However, there were persistent differences between species, as humans walked with less transverse plane pelvis rotation, less hip abduction, and greater peak anterior-posterior ground reaction force in late stance than chimpanzees. Our results suggest that human crouched-posture walking reproduces only a small subset of the characteristics of 3D kinematics and ground reaction forces of chimpanzee walking, with the remaining differences likely due to the distinct musculoskeletal morphologies of humans and chimpanzees.

Using Bayesian inference to estimate plausible muscle forces in musculoskeletal models.

BACKGROUND: Musculoskeletal modeling is currently a preferred method for estimating the muscle forces that underlie observed movements. However, these estimates are sensitive to a variety of assumptions and uncertainties, which creates difficulty when trying to interpret the muscle forces from musculoskeletal simulations. Here, we describe an approach that uses Bayesian inference to identify plausible ranges of muscle forces for a simple motion while representing uncertainty in the measurement of the motion and the objective function used to solve the muscle redundancy problem. METHODS: We generated a reference elbow flexion-extension motion and computed a set of reference forces that would produce the motion while minimizing muscle excitations cubed via OpenSim Moco. We then used a Markov Chain Monte Carlo (MCMC) algorithm to sample from a posterior probability distribution of muscle excitations that would result in the reference elbow motion. We constructed a prior over the excitation parameters which down-weighted regions of the parameter space with greater muscle excitations. We used muscle excitations to find the corresponding kinematics using OpenSim, where the error in position and velocity trajectories (likelihood function) was combined with the sum of the cubed muscle excitations integrated over time (prior function) to compute the posterior probability density. RESULTS: We evaluated the muscle forces that resulted from the set of excitations that were visited in the MCMC chain (seven parallel chains, 500,000 iterations per chain). The estimated muscle forces compared favorably with the reference forces generated with OpenSim Moco, while the elbow angle and velocity from MCMC matched closely with the reference (average RMSE for elbow angle = 2°; and angular velocity = 32°/s). However, our rank plot analyses and potential scale reduction statistics, which we used to evaluate convergence of the algorithm, indicated that the chains did not fully mix. CONCLUSIONS: While the results from this process are a promising step towards characterizing uncertainty in muscle force estimation, the computational time required to search the solution space with, and the lack of MCMC convergence indicates that further developments in MCMC algorithms are necessary for this process to become feasible for larger-scale models.

Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration.

A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

Fracture Resistance of Pressed and Milled Lithium Disilicate Anterior Complete Coverage Restorations Following Endodontic Access Preparation.

PURPOSE: This in vitro study evaluated the fracture resistance and clinical prognosis of anterior lithium disilicate crowns (e.max Press and e.max CAD), following endodontic access and repair. The research design simulates intraoral loading conditions to produce clinically applicable results. MATERIALS AND METHODS: Monolithic anterior crowns, based on #8 anatomy, were fabricated from e.max Press ingots and e.max CAD blocks and adhesively bonded on identical dies milled out of a dentin analog material (NEMA G10). Specimens were divided into 4 groups: intact pressed, repaired pressed, intact milled, and repaired milled (n = 15/group). Repaired pressed and repaired milled were prepared with a standardized endodontic access and repaired using a porcelain repair system and composite resin. All crowns were cyclically loaded under simulated oral conditions and then loaded to failure in water, using a universal testing machine. Data were interpreted using ANOVA/Tukey post-hoc test (α = 0.05). RESULTS: Mean loads to failure ranged from 758.9 to 931.4 N for the 4 groups, indicating that both fabrication techniques, pressed and milled, yielded restorations that could reasonably withstand maximum masticatory forces. The pressed groups (923.7 N) exhibited significantly higher fracture resistance than the milled groups (797.5 N), p = 0.0002. When milled and pressed groups were categorized into intact and repaired subgroups, no difference was found in fracture resistance between the subgroups. Differences were noted in the modes of fracture, where the milled groups (intact and repaired) exhibited higher frequency of catastrophic fractures than the pressed groups. CONCLUSIONS: Endodontic access preparation does not appear to affect fracture resistance of an anterior lithium disilicate restoration, suggesting that replacement may not be necessary. Fabrication technique had a significant effect on fracture resistance and fracture mode of lithium disilicate restorations. The pressed fabrication technique resulted in significantly greater crown strength and fracture resistance than the milled technique.